3Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada;

4Apeiron Biologics, Vienna, Austria;

5Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria;

6Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada;

7Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.

Corresponding author: Gavin Y. Oudit, gavin.oudit{at}ualberta.ca.

Abstract

OBJECTIVE Diabetic nephropathy is one of the most common causes of end-stage renal failure. Inhibition of ACE2 function accelerates
diabetic kidney injury, whereas renal ACE2 is downregulated in diabetic nephropathy. We examined the ability of human recombinant
ACE2 (hrACE2) to slow the progression of diabetic kidney injury.

RESEARCH DESIGN AND METHODS Male 12-week-old diabetic Akita mice (Ins2WT/C96Y) and control C57BL/6J mice (Ins2WT/WT) were injected daily with placebo or with rhACE2 (2 mg/kg, i.p.) for 4 weeks. Albumin excretion, gene expression, histomorphometry,
NADPH oxidase activity, and peptide levels were examined. The effect of hrACE2 on high glucose and angiotensin II (ANG II)–induced
changes was also examined in cultured mesangial cells.

CONCLUSIONS Treatment with hrACE2 attenuates diabetic kidney injury in the Akita mouse in association with a reduction in blood pressure
and a decrease in NADPH oxidase activity. In vitro studies show that the protective effect of hrACE2 is due to reduction in
ANG II and an increase in ANG 1–7 signaling.

Footnotes

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